Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase

Tawnya L. Bowles, Randie Kim, Joseph Galante, Colin M. Parsons, Subbulakshmi Virudachalam, Hsing Jien Kung, Richard J. Bold

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by ∼50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.

Original languageEnglish
Pages (from-to)1950-1955
Number of pages6
JournalInternational Journal of Cancer
Volume123
Issue number8
DOIs
Publication statusPublished - Oct 15 2008
Externally publishedYes

Fingerprint

Argininosuccinate Synthase
Pancreatic Neoplasms
Arginine
Cell Line
Growth
Citrulline
Neoplasms
Caspases
arginine deiminase
Eukaryotic Cells
Enzymes
Heterografts
Hepatocellular Carcinoma
Melanoma
Cell Death

Keywords

  • Arginine
  • Arginine deiminase
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. / Bowles, Tawnya L.; Kim, Randie; Galante, Joseph; Parsons, Colin M.; Virudachalam, Subbulakshmi; Kung, Hsing Jien; Bold, Richard J.

In: International Journal of Cancer, Vol. 123, No. 8, 15.10.2008, p. 1950-1955.

Research output: Contribution to journalArticle

Bowles, Tawnya L. ; Kim, Randie ; Galante, Joseph ; Parsons, Colin M. ; Virudachalam, Subbulakshmi ; Kung, Hsing Jien ; Bold, Richard J. / Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. In: International Journal of Cancer. 2008 ; Vol. 123, No. 8. pp. 1950-1955.
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